Connective tissue growth factor (CCN2) inhibits TNF-α-induced apoptosis by enhancing autophagy through the Akt and Erk pathways in osteoblasts.

: Connective tissue growth factor (CTGF/CCN2) is a secreted protein modulating various biological processes, such as proliferation, differentiation, and survival. Tumor necrosis factor-α (TNF-α), known as a proinflammatory factor, negatively regulates osteoblast differentiation and survival. However, the potential mechanisms of CCN2 in TNF-α-induced osteoblast apoptosis are not fully understood. In the present study, we found that CCN2 was expressed in osteoblasts and downregulated after treatment with TNF-α. Overexpression of CCN2 attenuated TNF-α-induced osteoblast apoptosis. Autophagy, a pro-survival biological behavior, was triggered by TNF-α stimulation, and CCN2 overexpression enhanced this process. Inhibition of autophagy by chloroquine (CQ) affected the anti-apoptotic effect of CCN2. Moreover, the phosphorylation levels of Akt and Erk were upregulated in CCN2-over expressed cells, and LY294002 and U1026 (which inhibited the Akt and Erk signaling pathways, respectively) reversed the effect of CCN2 on autophagy and cell survival enhancement. Our data suggest that CCN2 might be a positive regulator of osteoblast survival in TNF-α stimulation by enhancing autophagy through the Akt and Erk signaling pathways.